Review

23 pages, 1180 KiB

Open AccessReview

RNA 2′-O-Methylation (Nm) Modification in Human Diseases

by Dilyana G. Dimitrova, Laure Teysset and Clément Carré

Genes 2019, 10(2), 117; https://doi.org/10.3390/genes10020117 - 05 Feb 2019

Cited by 106 | Viewed by 11914

Nm (2′-O-methylation) is one of the most common modifications in the RNA world. It has the potential to influence the RNA molecules in multiple ways, such as structure, stability, and interactions, and to play a role in various cellular processes from epigenetic gene [...] Read more.

Nm (2′-O-methylation) is one of the most common modifications in the RNA world. It has the potential to influence the RNA molecules in multiple ways, such as structure, stability, and interactions, and to play a role in various cellular processes from epigenetic gene regulation, through translation to self versus non-self recognition. Yet, building scientific knowledge on the Nm matter has been hampered for a long time by the challenges in detecting and mapping this modification. Today, with the latest advancements in the area, more and more Nm sites are discovered on RNAs (tRNA, rRNA, mRNA, and small non-coding RNA) and linked to normal or pathological conditions. This review aims to synthesize the Nm-associated human diseases known to date and to tackle potential indirect links to some other biological defects. Full article

(This article belongs to the Special Issue The Epitranscriptome in Human Disease)

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17 pages, 2140 KiB

Open AccessReview

Eukaryotic 5-methylcytosine (m⁵C) RNA Methyltransferases: Mechanisms, Cellular Functions, and Links to Disease

by Katherine E. Bohnsack, Claudia Höbartner and Markus T. Bohnsack

Genes 2019, 10(2), 102; https://doi.org/10.3390/genes10020102 - 30 Jan 2019

Cited by 262 | Viewed by 16130

Abstract

5-methylcytosine (m⁵C) is an abundant RNA modification that’s presence is reported in a wide variety of RNA species, including cytoplasmic and mitochondrial ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs), as well as messenger RNAs (mRNAs), enhancer RNAs (eRNAs) and a number [...] Read more.

5-methylcytosine (m⁵C) is an abundant RNA modification that’s presence is reported in a wide variety of RNA species, including cytoplasmic and mitochondrial ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs), as well as messenger RNAs (mRNAs), enhancer RNAs (eRNAs) and a number of non-coding RNAs. In eukaryotes, C5 methylation of RNA cytosines is catalyzed by enzymes of the NOL1/NOP2/SUN domain (NSUN) family, as well as the DNA methyltransferase homologue DNMT2. In recent years, substrate RNAs and modification target nucleotides for each of these methyltransferases have been identified, and structural and biochemical analyses have provided the first insights into how each of these enzymes achieves target specificity. Functional characterizations of these proteins and the modifications they install have revealed important roles in diverse aspects of both mitochondrial and nuclear gene expression. Importantly, this knowledge has enabled a better understanding of the molecular basis of a number of diseases caused by mutations in the genes encoding m⁵C methyltransferases or changes in the expression level of these enzymes. Full article

(This article belongs to the Special Issue The Epitranscriptome in Human Disease)

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27 pages, 1030 KiB

Open AccessReview

Epitranscriptomic Signatures in lncRNAs and Their Possible Roles in Cancer

by Sorina Dinescu, Simona Ignat, Andreea Daniela Lazar, Carolina Constantin, Monica Neagu and Marieta Costache

Genes 2019, 10(1), 52; https://doi.org/10.3390/genes10010052 - 16 Jan 2019

Cited by 69 | Viewed by 6759

Abstract

In contrast to the amazing exponential growth in knowledge related to long non-coding RNAs (lncRNAs) involved in cell homeostasis or dysregulated pathological states, little is known so far about the links between the chemical modifications occurring in lncRNAs and their function. Generally, ncRNAs [...] Read more.

In contrast to the amazing exponential growth in knowledge related to long non-coding RNAs (lncRNAs) involved in cell homeostasis or dysregulated pathological states, little is known so far about the links between the chemical modifications occurring in lncRNAs and their function. Generally, ncRNAs are post-transcriptional regulators of gene expression, but RNA modifications occurring in lncRNAs generate an additional layer of gene expression control. Chemical modifications that have been reported in correlation with lncRNAs include m⁶A, m⁵C and pseudouridylation. Up to date, several chemically modified long non-coding transcripts have been identified and associated with different pathologies, including cancers. This review presents the current level of knowledge on the most studied cancer-related lncRNAs, such as the metastasis associated lung adenocarcinoma transcript 1 (MALAT1), the Hox transcript antisense intergenic RNA (HOTAIR), or the X-inactive specific transcript (XIST), as well as more recently discovered forms, and their potential roles in different types of cancer. Understanding how these RNA modifications occur, and the correlation between lncRNA changes in structure and function, may open up new therapeutic possibilities in cancer. Full article

(This article belongs to the Special Issue The Epitranscriptome in Human Disease)

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23 pages, 1539 KiB

Open AccessReview

Roles of Elongator Dependent tRNA Modification Pathways in Neurodegeneration and Cancer

by Harmen Hawer, Alexander Hammermeister, Keerthiraju Ethiraju Ravichandran, Sebastian Glatt, Raffael Schaffrath and Roland Klassen

Genes 2019, 10(1), 19; https://doi.org/10.3390/genes10010019 - 28 Dec 2018

Cited by 36 | Viewed by 6890

Abstract

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of [...] Read more.

Transfer RNA (tRNA) is subject to a multitude of posttranscriptional modifications which can profoundly impact its functionality as the essential adaptor molecule in messenger RNA (mRNA) translation. Therefore, dynamic regulation of tRNA modification in response to environmental changes can tune the efficiency of gene expression in concert with the emerging epitranscriptomic mRNA regulators. Several of the tRNA modifications are required to prevent human diseases and are particularly important for proper development and generation of neurons. In addition to the positive role of different tRNA modifications in prevention of neurodegeneration, certain cancer types upregulate tRNA modification genes to sustain cancer cell gene expression and metastasis. Multiple associations of defects in genes encoding subunits of the tRNA modifier complex Elongator with human disease highlight the importance of proper anticodon wobble uridine modifications (xm⁵U₃₄) for health. Elongator functionality requires communication with accessory proteins and dynamic phosphorylation, providing regulatory control of its function. Here, we summarized recent insights into molecular functions of the complex and the role of Elongator dependent tRNA modification in human disease. Full article

(This article belongs to the Special Issue The Epitranscriptome in Human Disease)

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19 pages, 273 KiB

Open AccessReview

RNA Editors, Cofactors, and mRNA Targets: An Overview of the C-to-U RNA Editing Machinery and Its Implication in Human Disease

by Taga Lerner, F. Nina Papavasiliou and Riccardo Pecori

Genes 2019, 10(1), 13; https://doi.org/10.3390/genes10010013 - 27 Dec 2018

Cited by 35 | Viewed by 7046

Abstract

One of the most prevalent epitranscriptomic modifications is RNA editing. In higher eukaryotes, RNA editing is catalyzed by one of two classes of deaminases: ADAR family enzymes that catalyze A-to-I (read as G) editing, and AID/APOBEC family enzymes that catalyze C-to-U. ADAR-catalyzed deamination [...] Read more.

One of the most prevalent epitranscriptomic modifications is RNA editing. In higher eukaryotes, RNA editing is catalyzed by one of two classes of deaminases: ADAR family enzymes that catalyze A-to-I (read as G) editing, and AID/APOBEC family enzymes that catalyze C-to-U. ADAR-catalyzed deamination has been studied extensively. Here we focus on AID/APOBEC-catalyzed editing, and review the emergent knowledge regarding C-to-U editing consequences in the context of human disease. Full article

(This article belongs to the Special Issue The Epitranscriptome in Human Disease)

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12 pages, 712 KiB

Open AccessReview

ADAR1 Editing and its Role in Cancer

by Li-Di Xu and Marie Öhman

Genes 2019, 10(1), 12; https://doi.org/10.3390/genes10010012 - 25 Dec 2018

Cited by 66 | Viewed by 9072

Abstract

It is well established that somatic mutations and escape of immune disruption are two essential factors in cancer initiation and progression. With an increasing number of second-generation sequencing data, transcriptomic modifications, so called RNA mutations, are emerging as significant forces that drive the [...] Read more.

It is well established that somatic mutations and escape of immune disruption are two essential factors in cancer initiation and progression. With an increasing number of second-generation sequencing data, transcriptomic modifications, so called RNA mutations, are emerging as significant forces that drive the transition from normal cell to malignant tumor, as well as providing tumor diversity to escape an immune attack. Editing of adenosine to inosine (A-to-I) in double-stranded RNA, catalyzed by adenosine deaminases acting on RNA (ADARs), is one dynamic modification that in a combinatorial manner can give rise to a very diverse transcriptome. Since the cell interprets inosine as guanosine (G), A-to-I editing can result in non-synonymous codon changes in transcripts as well as yield alternative splicing, but also affect targeting and disrupt maturation of microRNAs. ADAR-mediated RNA editing is essential for survival in mammals, however, its dysregulation causes aberrant editing of its targets that may lead to cancer. ADAR1 is commonly overexpressed, for instance in breast, lung, liver and esophageal cancer as well as in chronic myelogenous leukemia, where it promotes cancer progression. It is well known that ADAR1 regulates type I interferon (IFN) and its induced gene signature, which are known to operate as a significant barrier to tumor formation and progression. Adding to the complexity, ADAR1 expression is also regulated by IFN. In this review, we discussed the regulatory mechanisms of ADAR1 during tumorigenesis through aberrant editing of specific substrates. Additionally, we hypothesized that elevated ADAR1 levels play a role in suppressing an innate immunity response in cancer cells. Full article

(This article belongs to the Special Issue The Epitranscriptome in Human Disease)

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36 pages, 1316 KiB

Open AccessReview

tRNA-Derived Small RNAs: Biogenesis, Modification, Function and Potential Impact on Human Disease Development

by Vera Oberbauer and Matthias R. Schaefer

Genes 2018, 9(12), 607; https://doi.org/10.3390/genes9120607 - 05 Dec 2018

Cited by 80 | Viewed by 10109

Abstract

Transfer RNAs (tRNAs) are abundant small non-coding RNAs that are crucially important for decoding genetic information. Besides fulfilling canonical roles as adaptor molecules during protein synthesis, tRNAs are also the source of a heterogeneous class of small RNAs, tRNA-derived small RNAs (tsRNAs). Occurrence [...] Read more.

Transfer RNAs (tRNAs) are abundant small non-coding RNAs that are crucially important for decoding genetic information. Besides fulfilling canonical roles as adaptor molecules during protein synthesis, tRNAs are also the source of a heterogeneous class of small RNAs, tRNA-derived small RNAs (tsRNAs). Occurrence and the relatively high abundance of tsRNAs has been noted in many high-throughput sequencing data sets, leading to largely correlative assumptions about their potential as biologically active entities. tRNAs are also the most modified RNAs in any cell type. Mutations in tRNA biogenesis factors including tRNA modification enzymes correlate with a variety of human disease syndromes. However, whether it is the lack of tRNAs or the activity of functionally relevant tsRNAs that are causative for human disease development remains to be elucidated. Here, we review the current knowledge in regard to tsRNAs biogenesis, including the impact of RNA modifications on tRNA stability and discuss the existing experimental evidence in support for the seemingly large functional spectrum being proposed for tsRNAs. We also argue that improved methodology allowing exact quantification and specific manipulation of tsRNAs will be necessary before developing these small RNAs into diagnostic biomarkers and when aiming to harness them for therapeutic purposes. Full article

(This article belongs to the Special Issue The Epitranscriptome in Human Disease)

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21 pages, 1319 KiB

Open AccessReview

The Emerging Role of Epitranscriptomics in Cancer: Focus on Urological Tumors

by João Lobo, Daniela Barros-Silva, Rui Henrique and Carmen Jerónimo

Genes 2018, 9(11), 552; https://doi.org/10.3390/genes9110552 - 13 Nov 2018

Cited by 61 | Viewed by 5859

Abstract

Epitranscriptomics has gained ground in recent years, especially after the advent of techniques for accurately studying these mechanisms. Among all modifications occurring in RNA molecules, N6-methyladenosine (m⁶A) is the most frequent, especially among mRNAs. m⁶A has been demonstrated to [...] Read more.

Epitranscriptomics has gained ground in recent years, especially after the advent of techniques for accurately studying these mechanisms. Among all modifications occurring in RNA molecules, N6-methyladenosine (m⁶A) is the most frequent, especially among mRNAs. m⁶A has been demonstrated to play important roles in many physiological processes and several disease states, including various cancer models (from solid to liquid tumors). Tumor cells’ epitranscriptome is indeed disrupted in a way to promote cancer-prone features, by means of up/downregulating m⁶A-related players: the so-called writers, readers and erasers. These proteins modulate m⁶A establishment, removal and determine mRNAs fate, acting in a context-dependent manner, so that a single player may act as an oncogenic signal in one tumor model (methyltransferase like 3 (METTL3) in lung cancer) and as a tumor suppressor in another context (METTL3 in glioblastoma). Despite recent advances, however, little attention has been directed towards urological cancer. By means of a thorough analysis of the publicly available TCGA (The Cancer Genome Atlas) database, we disclosed the most relevant players in four major urogenital neoplasms—kidney, bladder, prostate and testicular cancer—for prognostic, subtype discrimination and survival purposes. In all tumor models assessed, the most promising player was shown to be Vir like m⁶A methyltransferase associated (VIRMA), which could constitute a potential target for personalized therapies. Full article

(This article belongs to the Special Issue The Epitranscriptome in Human Disease)

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